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Prognostic value of isocitrate dehydrogenase mutations in myelodysplastic syndromes: a retrospective cohort study and meta-analysis.

Jin J, Hu C, Yu M, Chen F, Ye L, Yin X, Zhuang Z, Tong H - PLoS ONE (2014)

Bottom Line: In addition, we discovered decitabine achieved a better therapeutic effect compared to other treatments in IDH mutation-positive patients (P = 0.023).The results from our study and the meta-analysis provide firm evidence that IDH mutations are significantly associated with poorer clinical outcomes in MDS.Additionally, hypomethylating agents may be an effective treatment option for MDS patients with IDH mutations.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, the First Affiliated Hospital of Zhejiang University, Hangzhou, People's Republic of China; Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.

ABSTRACT

Background: Recent genomic sequencing efforts have identified a number of recurrent mutations in myelodysplastic syndromes (MDS) that may contribute to disease progression and overall survival, including mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2).

Methods: Pretreatment bone marrow (BM) samples were acquired from mononuclear cells in 146 adult patients with de novo MDS from January 2006 to June 2013. Polymerase chain reaction (PCR) and direct sequencing were performed on exon 4 of IDH1/2 genes and mutation status was correlated with overall survival (OS) and leukemia-free survival (LFS). We then performed a meta-analysis combining previously published and current studies to explore the effect of IDH mutations on OS and LFS in MDS.

Results: In our study, somatic mutations of either IDH gene were discovered in 11 MDS patients (7.53%) and were significantly correlated with poorer OS (P = 0.007). IDH mutations were specifically associated with a poorer OS in the intermediate-1 risk group by the International Prognostic Scoring System (IPSS) (P = 0.039). In addition, we discovered decitabine achieved a better therapeutic effect compared to other treatments in IDH mutation-positive patients (P = 0.023). We identified six previous studies of IDH mutations in MDS. A meta-analysis of these studies included 111 MDS patients IDH mutations and 1671 MDS patients with wild-type IDH1/2. The hazard ratios (HRs) of OS and LFS for patients with IDH mutations were 1.62 (95% CI, 1.27-2.09) and 2.21 (95% CI, 1.48-3.30), respectively.

Conclusion: The results from our study and the meta-analysis provide firm evidence that IDH mutations are significantly associated with poorer clinical outcomes in MDS. Identification of IDH mutations may be pivotal for better risk stratification in MDS patients and improving IPSS score. Additionally, hypomethylating agents may be an effective treatment option for MDS patients with IDH mutations.

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Kaplan–Meier survival curves for survival of MDS patients.(A) Overall survival data for MDS patients stratified by IDH1/2 mutational status. (B) Leukemia-free survival data for MDS patients stratified by IDH1/2 mutational status. (C) Overall survival data for MDS patients stratified by IDH1 mutational status. (D) Leukemia-free survival data for MDS patients stratified by IDH1 mutational status. (E) Overall survival data for MDS patients stratified by IDH2 mutational status. (F) Leukemia-free survival data for MDS patients stratified by IDH2 mutational status.
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pone-0100206-g002: Kaplan–Meier survival curves for survival of MDS patients.(A) Overall survival data for MDS patients stratified by IDH1/2 mutational status. (B) Leukemia-free survival data for MDS patients stratified by IDH1/2 mutational status. (C) Overall survival data for MDS patients stratified by IDH1 mutational status. (D) Leukemia-free survival data for MDS patients stratified by IDH1 mutational status. (E) Overall survival data for MDS patients stratified by IDH2 mutational status. (F) Leukemia-free survival data for MDS patients stratified by IDH2 mutational status.

Mentions: The median survival time was 512 days (range 100–924 days) in the IDH1/2 mutant group and 956 days (range, 632–1280 days) in the wild-type IDH1/2 group. Survival analysis demonstrated MDS patients harboring IDH1/2 mutations had significantly shorter OS compared to patients with wild-type IDH1/2 (P = 0.007) (Figure 2A). Further, we found IDH1 mutations negatively affected OS in MDS (P = 0.030) rather than IDH2 mutations (P = 0.067) (Figure 2C, E). The presence of IDH1/2 mutations did not influence the LFS (P = 0.078, 0.195 and 0.201, respectively) (Figure 2B, D, F). Interestingly, our data showed the presence of IDH1/2 mutations was an adverse predictor of OS in the intermediate-1 risk group of IPSS (P = 0.039) (Figure 3A), but not in the intermediate-2 risk (P = 0.410) (Figure 3B) or high risk (P = 0.685) (Figure 3C) group. Our results also indicated that decitabine achieved a better therapeutic effect in IDH1/2 mutation-positive patients compared to other treatments (including: GHA regimen, n = 3; GAA regimen, n = 2; supportive care, n = 2) (P = 0.023) (Figure 3D).


Prognostic value of isocitrate dehydrogenase mutations in myelodysplastic syndromes: a retrospective cohort study and meta-analysis.

Jin J, Hu C, Yu M, Chen F, Ye L, Yin X, Zhuang Z, Tong H - PLoS ONE (2014)

Kaplan–Meier survival curves for survival of MDS patients.(A) Overall survival data for MDS patients stratified by IDH1/2 mutational status. (B) Leukemia-free survival data for MDS patients stratified by IDH1/2 mutational status. (C) Overall survival data for MDS patients stratified by IDH1 mutational status. (D) Leukemia-free survival data for MDS patients stratified by IDH1 mutational status. (E) Overall survival data for MDS patients stratified by IDH2 mutational status. (F) Leukemia-free survival data for MDS patients stratified by IDH2 mutational status.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061070&req=5

pone-0100206-g002: Kaplan–Meier survival curves for survival of MDS patients.(A) Overall survival data for MDS patients stratified by IDH1/2 mutational status. (B) Leukemia-free survival data for MDS patients stratified by IDH1/2 mutational status. (C) Overall survival data for MDS patients stratified by IDH1 mutational status. (D) Leukemia-free survival data for MDS patients stratified by IDH1 mutational status. (E) Overall survival data for MDS patients stratified by IDH2 mutational status. (F) Leukemia-free survival data for MDS patients stratified by IDH2 mutational status.
Mentions: The median survival time was 512 days (range 100–924 days) in the IDH1/2 mutant group and 956 days (range, 632–1280 days) in the wild-type IDH1/2 group. Survival analysis demonstrated MDS patients harboring IDH1/2 mutations had significantly shorter OS compared to patients with wild-type IDH1/2 (P = 0.007) (Figure 2A). Further, we found IDH1 mutations negatively affected OS in MDS (P = 0.030) rather than IDH2 mutations (P = 0.067) (Figure 2C, E). The presence of IDH1/2 mutations did not influence the LFS (P = 0.078, 0.195 and 0.201, respectively) (Figure 2B, D, F). Interestingly, our data showed the presence of IDH1/2 mutations was an adverse predictor of OS in the intermediate-1 risk group of IPSS (P = 0.039) (Figure 3A), but not in the intermediate-2 risk (P = 0.410) (Figure 3B) or high risk (P = 0.685) (Figure 3C) group. Our results also indicated that decitabine achieved a better therapeutic effect in IDH1/2 mutation-positive patients compared to other treatments (including: GHA regimen, n = 3; GAA regimen, n = 2; supportive care, n = 2) (P = 0.023) (Figure 3D).

Bottom Line: In addition, we discovered decitabine achieved a better therapeutic effect compared to other treatments in IDH mutation-positive patients (P = 0.023).The results from our study and the meta-analysis provide firm evidence that IDH mutations are significantly associated with poorer clinical outcomes in MDS.Additionally, hypomethylating agents may be an effective treatment option for MDS patients with IDH mutations.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, the First Affiliated Hospital of Zhejiang University, Hangzhou, People's Republic of China; Institute of Hematology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.

ABSTRACT

Background: Recent genomic sequencing efforts have identified a number of recurrent mutations in myelodysplastic syndromes (MDS) that may contribute to disease progression and overall survival, including mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2).

Methods: Pretreatment bone marrow (BM) samples were acquired from mononuclear cells in 146 adult patients with de novo MDS from January 2006 to June 2013. Polymerase chain reaction (PCR) and direct sequencing were performed on exon 4 of IDH1/2 genes and mutation status was correlated with overall survival (OS) and leukemia-free survival (LFS). We then performed a meta-analysis combining previously published and current studies to explore the effect of IDH mutations on OS and LFS in MDS.

Results: In our study, somatic mutations of either IDH gene were discovered in 11 MDS patients (7.53%) and were significantly correlated with poorer OS (P = 0.007). IDH mutations were specifically associated with a poorer OS in the intermediate-1 risk group by the International Prognostic Scoring System (IPSS) (P = 0.039). In addition, we discovered decitabine achieved a better therapeutic effect compared to other treatments in IDH mutation-positive patients (P = 0.023). We identified six previous studies of IDH mutations in MDS. A meta-analysis of these studies included 111 MDS patients IDH mutations and 1671 MDS patients with wild-type IDH1/2. The hazard ratios (HRs) of OS and LFS for patients with IDH mutations were 1.62 (95% CI, 1.27-2.09) and 2.21 (95% CI, 1.48-3.30), respectively.

Conclusion: The results from our study and the meta-analysis provide firm evidence that IDH mutations are significantly associated with poorer clinical outcomes in MDS. Identification of IDH mutations may be pivotal for better risk stratification in MDS patients and improving IPSS score. Additionally, hypomethylating agents may be an effective treatment option for MDS patients with IDH mutations.

Show MeSH
Related in: MedlinePlus